Accelerated atherosclerosis of extramural coronary arteries has been considered the major factor underlying cardiac mortality in diabetes mellitus. More recent autopsy data indicate that the incidence and severity of coronary atherosclerosis in diabetics may not be substantially greater than in nondiabetic subjects. For this reason primary myocardial disease (cardiomyopathy) is receiving increased attention as a major cause of cardiac failure and death in diabetic individuals. We have described ventricular hypertrophy and degenerative lesions in the myocardium, intramural coronary arteries and perivascular nerves of the genetically diabetic mouse C57BL/ksJ db/db that constitute a cardiomyopathy. The primary event appears to be the autophagocytosis of mitochondria and lipid droplets and their conversion into large residual bodies. The accumulation of these bodies is due to a reduction in the activities of lysosomal enzymes, particularly those involved in hydrolysis of membrane constituents, (e.g., B-glucuronidase, aryl sulphatase and N-acetyl-B-glucosaminidase). It is our working hypothesis that a biochemical lesion in cardiac mitochondria of the db/db mouse results in lipid accumulation. The subsequent myocytolysis may be mediated by cathepsins B and D myofibrillar protease. We propose to test this hypothesis by studying cardiac mitochondrial function in db/db mice by measuring cytochrome oxidase and ATPase activity, and fatty acid oxidation and di- and triglyceride synthesis. Lysosomal and nonlysosomal cardiac protease activities will also be assayed. Autonomic and pacemaker tissues will be examined by light and electron microscopy. Histochemistry and cytochemistry will be used to identify subpopulations of cardiac lysosomes. Morphometry will be used to quantitate ventricular hypertrophy. Autoradiography (3H-thymidine) will be utilized to establish a labeling index for endothelial and smooth muscle cells of intramyocardial arteries and endothelial and perivascular cells of myocardial capillaries and venules. Lanthanum will test the functional integrity of cardiocytes. The permeability of myocardial vasculature will be examined using tracers. We shall also investigate the protective effects on myocardium of dietary restriction and insulin administration.